Carbamic acid esters of benzionidazoles

ABSTRACT

Carbamic acid esters are provided which, inter alia, have anthelmintic action against nematodes and fungicidal activity against Aspegillus niger, fumigatus and nidulans, Trichophyton species and Candida albicans at concentrations as low as 4 gamma /ml. The esters have the formula:   Y is hydrogen or alkyl, A and B are the same or different and are each hydrogen, halogen, nitro, lower alkyl or lower alkoxy, M AND N ARE 1 OR 2, AND R is substituted or unsubstituted aliphatic, aralkyl, aryl or heterocyclic, and are prepared by reacting an amine of the formula:   Y is hydrogen or alkyl, A and B are the same or different and are each hydrogen, halogen, nitro, lower alkyl or lower alkoxy, and M AND N ARE 1 OR 2, WITH A CARBONIC ACID DERIVATIVE OF THE FORMULA: IN WHICH R is unsubstituted or substituted aliphatic, aralkyl, aryl, or a heterocyclic radical, and D is halogen, OR1 or WHEREIN R1 and R2 are the same or different and have any of the above meanings of R, or R and D further being the residual constituents of the ring system of glycol carbonate and benzocatechol carbonate.

United States Patent [72] lnventors Walter Gauss Cologne-Stammheim;Heinz Herlinger, Korb/Waiblingen; Herbert Thomas, Wuppertal-Elberield;Manfred Plempel, Wuppertal-Elberfeld, all

of Germany [21] Appl. No. 753,716

[22] Filed Aug. 19, 1968 [45] Patented Sept. 28,1971

[73] Assignee Farbenfabriken Bayer Aktiengesellschait Leverkusen,Germany [32] Priority Aug. 29, 1967 [3 3] Germany [31] F 53346IVd/12p[54] CARBAMIC ACID ESTERS OF BENZIONIDAZOLES 17 Claims, N0 Drawings [52]US. Cl 260/309.2, 424/273 [51] int. Cl C07d 49/38 [50] Field of Search260/309.2, 482 C [56] References Cited UNITED STATES PATENTS 2,755,2867/1956 Bell et a1 260/482C 2,876,090 3/1959 Lecper et al. 260/482 C2,933,502 4/1960 Klopping 260/3092 3,226,426 12/1965 Hopkins et a1260/482 C 3,238,036 3/1966 260/482C 3,325,506 6/1967 260/309.2 3,458,5287/1969 260/309 FOREIGN PATENTS 960,538 6/1964 Great Britain 260/482 C396,870 1/1966 Switzerland 260/482 C OTHER REFERENCES Adams et a1. Chem.Rev. Vol. 65, pages 569- 573 relied on (1965 QD1.A563

Larrouquere Bul. Soc. Chim. (France) A64, page 1543 QDl.S4

Murfitt German Application 1,051,842 3- 1959 (120 17/01 (2 page spec.)260- 482 C Ridi et al. Ann. Chim. (Rome) Vol. 44, pages 28- 38 (1954)copy in group 120, 260- 309.2

Rosnati Bul. Soc. Chim (France) 1964, page 1542 QDl.S4

Primary Examiner-Natalie Trousof Attorney-Jacobs & Jacobs ABSTRACT:Carbamic acid esters are provided which, inter alia, have anthelminticaction against nematodes and fungicidal activity against Aspegillusniger, fumigatus and nidulans, Trichophyton species and Candida albicansat concentrations as low as 4 y/ml. The esters have the formula:

T is hydrogen or alkyl,

A and B are the same or different and are each hydrogen, halogen, notro.lower alkyl or lower alkoxy.

m and n are 1 or 2, and

R is substituted or unsubstituted aliphatic. aralkyl. aryl orheterocyclic, and are prepared by reacting an amine of the formula:

n which Y is hydrogen or alkyl,

A and B are the same or different and are each hydrogen. halogen. notro.lower alkyl or lower alkoxy. and

m and n are 1 or2. with a carbonic acid derivative of the formula:

in which R is unsubstituted or substituted aliphatic, aralkyl. aryl, ora heterocyclic radical. and

D 18 halogen. OR 1 or ii wherein R and R'- are the same or different andhave any of the above meanings of R. or

R and D further being the residual constituents of the ring system ofglycol carbonate and benzocatechol carbonate.

CARBAMIC ACID ESTERS F BENZIONIDAZOLES it has now been found that novelcarbamic acid esters of benzimidazoles are obtained by reacting an amineof the formula:

in which Y is hydrogen or alkyl, A is hydrogen, halogen, nitro or loweralkyl or lower alkoxy, B is the same as or different from A, and m and nare each I or 2, in per se known manner with a carbonic acid derivativeof the formula:

in which R is a substituted or unsubstituted aliphatic, aralkyl or arylradical or a heterocyclic radical, and D is halogen, OR or R and R arethe same or different and have any of the above meanings of R; R and Dmay further be the residual constituents of the ring system of glycolcarbonate or benzocatechol carbonate, followed, if desired, bysubsequent transesterification.

The alkyl radicals (Y) comprise straight-chain or branched radicals withl-l2, preferably l-6, carbon atoms. The preferred halogen atoms (A or B)are fluorine, chlorine and bromine.

Amines which are used for the process are, for example:

2-[pyrazolyl-( l )]-4-amino-benzimidazole 2-[ 3-methyl-pyrazolyl-( l)]-4-amino-benzimidazole 2-[5-methyl-pyrazolyl-( l)l-4-amino-benzimidazole 2-[3,5-dimethyl-pyrazolyl-( l)]-4-amino-benzimidazole 2-[4-chloro-pyrazolyl-( l)1-4-amino-benzimidazole 2-[4-bromo-pyrazolyl-( l)]-4-amino-benzimidazole 2-[4-methoxy-pyrazolyl-( l)]-4-amino-benzimidazole 2-[4-methoxy-ethoxy-pyrazolyl-( l)]4-aminobenzimidazole 2-[pyrazolyl-(1)]-5-amino-benzimidazole 2-[3-methyl-pyrazolyl-( 1)]5-amino-benzimidazole 2-[5-methyl-pyrazolyl-( l)]-5-amino-benzimidazole 2-[3,5-dimethyl-pyrazolyl-( l)]-5-amino-benzimidazole 2-[ 4-chloro-pyrazolyl-( l)1-5-amino-benzimidazoie 2-[4bromo-pyrazolyl-( l)]-5-amino-benzimidazole 2-[4methoxy-pyrazolyl-( l)]-5-amino-benzimidazole 2-[4-methoxy-ethoxy-pyrazolyl-( l)]-5-aminobenzimidazole l-methyl-2-[pyrazolyl-( l)I-S-amino-benzimidazole l-methyl-2-[pyrazolyl-( l)]-6-amino-benzimidazole and l-methyl-2-[pyrazolyl-( l)]-7-amino-benzimidazole.

The amines used as starting compounds can be obtained by known processes(Belgian Pat. No. 656,016).

The optionally substituted aliphatic radicals (R) comprise alkylradicals with 1-20 carbon atoms, preferably l-6 carbon atoms, which maybe straight-chain or branched and may contain a double bond, as well ascorresponding cycloaliphatic radicals with 3-12, preferably five, six oreight carbon atoms, especially 5-6 carbon atoms, in the ring system. Theoptionally substituted aralkyl radicals (R) preferably comprise thosewith 6 or 10 carbon atoms in the aromatic part and i-4 carbon atoms inthe chain. The optionally substituted aryl radicals (R) comprise thosewith up to l0 carbon atoms in the ring system, preferably the benzeneradical.

Examples of substituents in the aliphatic or aromatic radical arehalogens (preferably fluorine, chlorine or bromine),

hydroxy, carboxy, carbalkoxy with up to six carbon atoms in the alkylradical, alkoxy (preferably l-4 carbon atoms), and the dialkylaminoradical with up to 10 carbon atoms (preferably l-4 carbon atoms) in bothalkyl radicals. The aromatic radical may further be substituted by alkylgroups (preferably of l-4 carbon atoms) and by nitro groups (preferablyonly one).

Substituents in the aromatic part of the aralkyl radical are theaforesaid halogens (preferably fluorine, chlorine or bromine), alkylgroups (preferably of l-4 carbon atoms), alkoxy groups (preferably ofl-4 carbon atoms), and the nitro group. Heterocyclic radicals (R) areprimarily those with five or six ring members which may contain up tothree identical or different hetero atoms. Besides oxygen and sulphur,the hetero constituent may also be the N-alkyl radical (preferably withup to eight carbon atoms). Heterocycles with one (or at most two) oxygenor sulfur atoms, in addition or not to nitrogen or an N-alkyl radical,are preferred.

Carbonic acid derivatives which are used for the process (cf.Houben-Weyl, Methoden der organischen Chemie, 4th Edition, Volume Vlll,pages 137 et seq. and 10] et seq.) are for example: the methyl ester,ethyl ester, fi-chloroethyl ester, n-propyl ester, isopropyl ester,n-butyl ester, isobutyl ester, tert.-butyl ester, n-amyl ester, dodccylester, benzyl ester, phenethyl ester, cyclohexyl ester, phenyl ester,a-naphthyl ester and the B-naphthyl ester of chlorocarbonic acid.

Examples of pyrocarbonic acid esters are pyrocarbonic acid di-methylester, di-ethyl ester, di-n-propyl ester, di-isopropyl ester, anddi-nbutyl ester. Apart from these symmetrical pyrocarbonic aciddi-esters, asymmetrical pyrocarbonic acid di-esters can also be used,such as are described in Liebigs Annalen der Chemie, 624, 30-36 1959).

Examples of such compounds are: methyl-ethyl pyrocarbonic acid ester,l3-chloroethyl-ethyl-pyr0carbonic acid ester, allyl-ethyl-pyrcarbonicacid ester, B-methoxyethyl-pyrocarbonic acid ester,benzyl-ethyl-pyrocarbonic acid ester, cyclohexyl-ethyl-pyrocarbonic acidester, and phenyl-ethylpyrocarbonic acid ester.

When pyrocarbonic acid di-estcrs of asymmetrical structure are used, thelower alkyl radical, according to experience, is predominantly split offas an alkanol in the reaction with the amines, and there is formed thecarbamic acid ester of the higher hydroxy compounds, for example:

H H 0 o ---NH-o-o-@ canon 00,

Carbonic acid di-esters, such as diethyl carbonate or diphenyl carbonatealso react with the amines to form the desired urcthanes according tothe following general equation:

The process can also be extended to carbonic acid esters of cyclicstructure, such as glycol carbonate or benzocateehol carbonate. in thecase of the two last-mentioned compounds, the amines are converted intothe corresponding carbamic acid-B-hydroxy-ethyl esters and carbamicacid-ortho-hydroxyphenyl esters:

3 4 The products produced by the process are isolated and purified byper se known methods. They are mostly obtained in NH2 :0 N solid formand are characterized by an unlimited storability.

\ 0 The new compounds which can be obtained by the present 0 processcorrespond to the formula:

HO As esters, the new urethanes the preparation of which has 4 beendescribed in greater detail above are suitable for R transesterificationreactions. it is possible, for example, to l [I (3) convert the carbamicacid aryl esters of the formula -NH-CO- 0 O-aryl where aryl can denote,for instance, a phenyl radical, (Mm l with compounds containingaliphatically linked hydroxyl to form new urethanes:

. in which the radicals A, B. Y, R, m and n have the same meanl ing asabove.

-NH(|?,Oa.ryl H0 |3 -NH(fiO |3- 8YY1 OH The new compounds are useful forhuman and veterinary O 0 medicine. They exhibit favorable effects in thecase of worm infections, especially against nematodes. They also havefun- Clearly, it is possible to exchange in the urethanes gicidaleffects against Aspcrgillus niger, Aspcrgillus fumigatus, Aspergillusnidulans and against Trichophyton species and NH C O- R Candida albicansat concentrations as low as 4 gamma per milll liliter. The route ofadministration and mode of use in u vehi- O cle or carrier is the sameas with known active agents.

The following tables Nos. l and 2 represent the anthelmina lower alkylradical R for a higher, optionally substituted tic effect of the newcompounds produced in accordance with alkyl radical. working examples Iand 7.

Dos. in nuz./kg./rr luction of parasites in porcunt {found aftersection) Strains of parasites Stage Therapy Compound 1,000 500 250 10025 10 5 4xp.o 7. Hymenopepis Yuma-M Adult gigs-- i' 5xs.c...2-'lhi:iz..... Hymenolepisdiminuta-R Adult... Hlgggg g g 5xp.o 1Hymenolepis microstoma-M Adult 5xp.o 2-Iliia7...v

5xsc. ..1. Cysticercus-M Larvae. 5xp.o

- t c l. Adult........... 'f' ff Strongyloides ratti-R AdulL.

Asearis-Larvae-M Larvae... Aspiculuris-M (Oxyura) Adult.

Syphacia-IVI (0xyura)... Adult v Heterakis-M Adult 4 gatin ..%x .o. 1

Larvae 1x p.o. (38 hours}.. 1.

Larvae (4/5)" 1x p.0. (96 hours). 1 Neniatospiroides-M gggg aTrichinella-M (Gut-stage) AdulL. i: 7 Triehinella-M (Muscle-stage)...Larvae" 4 L' Triehuris-M Adult NOTE:2-Thiaz.=2-[Thiazo1yl-(4)]bei1zimidazole for comparison; 1=Ethylesteraccording to Example 1; 7= Isopropylrstcr according to Example 7.

Dosv in rue/kg. per 05 reduction of parasites Stage respectively] inpvrcvnt after suction age of infection at e e e 7 Host Parasite time oftreatment Example N0. 100 50 40 25 20 10 7 100 100 8487 83-96 (ill-U430-51 Sheep... Haemonchuscontort'ua.. Adult/2l44days ...{1. J8 J1Thiabv-uduzoL. 100 100 100 74-88 38-8 no 61-72 Sheep"... Huemrmchuscontort'us-.. 5. Larvae/12 days {1 UT 41 Thiabi-nduzoLu 100.. v

7 )6 Z2TS Sheep... Haemonchus contortux. 4. Larvae/6 day5 .{1 35Thiabondazol... J -10!] on my 0 Sheep"... Trzchostmngylus colubrzformm.Adult/21-22 days....{ 7 7 7 7 7 7 V V h 100 H 78 .l' Sheep...'1rich0strongylus colubrifonnis. 5. Larvae/12days.uiz fiidbbh'd biii 6 gw i """:::::l

Sheep-.. Trichostrongylus colubrifurmz's.. 4. Larvae/6 days.-. {z qf i ih'ddibii l: 1 100 Table Coniinued Dose in mgJkg. per 05 reduction ofparasites Stage respectively/ in percent after section age of infectionat Host Parasite time of treatment Example No. 100 80 50 40 25 20 10Sheep Ostertagia CifLU77lCi71Cia Adu1t/21-22 days...{z z m 38 w SheepOstertagia circumcz'ncta... 5. Larvae/12 days...{k Sheep"... Ostertagz'acircumcinda 4. Larvae/6 days ..iffi ad ib ljI II: V j Sheep...Oesophagostizmumcolumbi- Adult/52 days 7 100 anum. Sheep oesophagustomumcolumbi- 4. Larvae/21 days". 7

anum. Shee Oeso hagostommn columbi- 7 H p Oaniim. l Lame/12"-{ThiabendazoL Shee esophagostomumco umbil7 p anum. Larvaelfi ""l1hia1mndaz Sheep"... Strongyloides papilldrus" Adult/9 days i5 i Sheep.v Bunostomum trigonocephalmm. Adult/82 days 7 13 Adult '21 days. 7 V CowCooperia punctata 5. Larvae/l2 days...

4. Larvae/6 days Pig Strongyloides ransomi Adult/10 days Similar goodeffects are obtained with the other compounds in accordance with theinvention.

EXAMPLE 1 40.5 g. (0.25 mole) of pyrocarbonic acid diethyl ester areadded dropwise within 1 hour to a suspension consisting of 39.8 g. (0.2mole) of 2-[pyrazolyl-( 1 )]-amino-benzimidazole and 100 ml. of ethanol.With the evolution of CO a solution is initially formed, from which thereaction product is later precipitated. On the following day there areadded 150 ml. of petroleum ether, the product is filtered off withsuction, washed with petroleum ether and dried. Yield: 49.9 g. of thecompound ofthe formula:

For analysis, a sample was recrystallized from boiling ethylacetate/light petrol and dried at 1 C C, H,;,N O (molecular weight271.27)

Calculated: C 57.56% H 4.83% N 25.82% 0 11.80% Found: C 57.57% H 5.08 N25.35 012.45%

The 2-[pyrazolyl-(1)]-5-amino-benzimidazole used as starting materialwas obtained as follows:

203.5 g. of 2-[pyrazolyl-(1)]-5-nitro-benzimidazole (prepared accordingto Belgian Pat. No. 65 6,016) are hydrogenated in 2 liters of dimethylformamide in the presence of 80 g. of Raney nickel at 60 C. withhydrogen under a maximum pressure of 60 atmospheres gauge, until theabsorption of gas is terminated. The mixture is filtered off withsuction from the catalyst and concentrated in a water jet vacuum,finally at 95 C.

The residue crystallizes slowly. There are obtained 175 g. of crudeproduct of m.p. 181-182 C., which can be recrystallized from water withthe addition of charcoal for purification. The compound then melts at185186 C.

EXAMPLE 2 53.2 g. (0.25 mole) of 1-methy1-2-[pyrazolyl-( 1)]-5-amin0benzimidazole are dissolved in 250 ml. of ethanol by heating. Thesolution is cooled to room temperature and 50.6 g. (0.3125 mole) ofpyrocarbonic acid diethyl ester are added dropwise within 30 minuteswhile stirring. A thick slurry is formed, to which a further 50 ml. ofethanol are added. The reaction is completed by bringing the mixture tothe boil once. After cooling to 0 C. the reaction product is filteredoff with suction, and washed with ethanol at 20" C. There are obtained62.5 g. of the compound of the formula:

m.p. 164.5-165.5C.

After recrystallization from ethanol: m.p. 167168 C. C, H, N .;O(molecular weight 258.30)

Calculated: C 58.93% H 5.30% N 24.55% 0 11.22% Found: C 58.8% H 5.3% N24.7% 011.2%

The 1-methyl-2-[pyrazolyl-(1)]-5-amino-benzimidazole used as startingmaterial was obtained as follows:

24.3 g. (0.1 mole) of 1-methy1-2-[pyrazolyl-(l)]-5-nitrobenzimidazole(m.p. 217.5-2l9 C.) which can be obtained by analogy with the processdescribed in Belgian Pat. No. 656,016 from1methyl-Z-hydrazino-Snitro-benzimidazolc by condensation withl,1,3,3-tetramethoxy-propane, are hydrogenated in 150 ml. of dioxan withhydrogen in the presence of 5 g. of Raney nickel as catalyst at 20 C.and a maximum pressure of 40 atmospheres gauge, until the absorption ofgas is terminated. The mixture is separated from the catalyst, thesolvent is removed in a water jet vacuum at a maximum bath temperatureof C., and 19.2 g. of crude product of m.p. 127-128 C. are obtained asresidue. By recrystallizing once from toluene with the addition ofcharcoal and drying at 1 10 C., there is obtained the completely pureamino compound ofm.p. l30.51 3 1 C.

C H N (molecular weight 213.24) Calculated: C 61.95% H 5.20% N 32.85%Found: C 62.0% H 5.4% N 33.1%

EXAMPLE 3 17.8 g. (0.11 mole) of pyrocarbonic acid diethyl ester areadded in one jet at 05 C., while stirring, to a mixture of 19.9 g. (0.1mole) of Z-[pyrazolyl-(l)l-4-amino-benzimidazole and ml. of ethanol, andthe cooling bath is removed. On the following day the reaction mixturewhich has become thick is mixed with 50 ml. of ethanol, brought to theboil and allowed to cool. The precipitated reaction product is finallyisolated at 0 C. and dried at 1 10 C. There are obtained 20.0 g. of thecompound of the formula:

. and m.p. 186187 C.

26.1 g. of 2-[pyrazolyl-(1)]-4nitro-benzimidazole which 10 can beobtained by analogy with the process described in Belgian Pat. No.656,016 from 2-hydrazino-4-nitrobenzimidazole by condensation withl,l,3,3-tetramethoxypropane, are hydrogenated in 170 ml. of dioxan inthe presence of 10 g. of Raney nickel with hydrogen at 40 C. and amaximum pressure of 50 atmospheres gauge, until the absorption of gas isterminated. The mixture is separated from the catalyst and freed fromthe solvent in a water jet vacuum. As residue there is obtained abrittle resin which is dissolved at 50 C. in 228 ml. of 1N HCl.Impurities are removed by means of charcoal. Sodium bicarbonate is thenslowly added with stirring until the pH is 7, the precipitated aminocompound is filtered off with suction and recrystallized from plenty ofwater with the addition of charcoal. For analysis, the product was driedin a vacuum at 100 C. over P until the weight remained constant; m.p.156.5158 C. C H N (molecular weight 199.21 Calculated: C 60.29% H 4.55%N 35.16% Found: C 60.2% H 4.5% N 35.3%

The other amines used for the process can be obtained in an analogousmanner.

EXAMPLE 4 22.1 g. (0.165 mole) of pyrocarbonic acid dimethyl ester areadded dropwise within 1 hour while stirring to a suspension consistingof 29.85 g. (0.15 mole) of 2-[pyrazolyl-( 1 )]-5 amino-benzimidazole and60 ml. of methanol. During that time the mixture initially becomesthinner and then again very thick. To achieve a better mixing effect afurther 165 ml. of methanol are added. After cooling on the followingday to -20 C., the reaction product is filtered off with suction, washedwith methanol of60 C. and dried at 1 C. 33.8 g. of the compound of theformula:

omo-p-ms- H EXAMPLE 5 40.9 g. (88 percent) of pyrocarbonicacid-di-n-butyl ester (0.165 mole) are added dropwise within 40 minuteswhile stirring to a suspension consisting of 29.85 g. (0.15 mole) of 2-of melting point 173.5175 C. are obtained. By a single recrystallizationstep from 10 times the quantity of chlorobenzene the melting point israised to l75.5176 C. C H N O (molecular weight 299.33)

Calculated: C 60.19% H 5.72% N 23.40% 0 10.69%

Found: C 60.7% H 6.1% N 22.8% 010.7%

EXAMPLE 6 47.5 g. (0.25 mol) of pyrocarbonic acid-di-npropyl ester areadded dropwise within 50 minutes to a suspension consisting of 39.8 g.(0.2 mol) of 2-]pyrazolyl-(l)]-5-aminobenzimidazole and ml. ofn-propanol. A clear solution is obtained which is solidified to a thickpaste after inoculation. On the following day the paste is stirred with750 ml. of ligroin. The reaction product is filtered off with suctionand dried at 1 10 C. 54.8 g. of the compound of the formula of meltingpoint 171 .5-172.5 C. are obtained. The product can be recrystallizedfrom hot n-propanol/hot ligroin. The melting point remains howeverunchanged.

C H N O (molecular weight 285.30)

Calculated: C 58.93% H 5.30% N 24.55% 0 11.22%

Found: C 58.8% H 5.5% N 24.424.4% O 11.6%

EXAMPLE 7 62.7 g. (0.33 mol) of pyrocarbonic acid di-isopropyl ester areadded dropwise within 20 minutes while stirring to a suspensionconsisting of 59.7 g. (0.3 mol) of 2-[pyrazolyl-(l)]-5-amino-benzimidazole and 300 cc. of iso-propanol. First a clearsolution is obtained, from which the desired product is separated off.On the following day the product is isolated while cooling with ice anddried at 1 10 C. 57.9 g. of the compound of the formula of melting pointl80.5 to 181.5 C. are obtained. C H N O (molecular weight 285.30)

Calculated C 58.93% H 5.30% N 24.55% 0 11.22% Found: C 58.9% H 5.4% N24.3%O11.7%

EXAMPLE 8 A suspension consisting of 45.8 g. (0.2 mol) of 2-[4-methoxy-pyrazolyl-( l )]-5-amino-benzimidazole and 200 ml. of ethanolare reacted dropwise while stirring with 35.64 g. (0.22 mol) ofpyrocarbonic acid diethyl ester. First the starting material isdissolved and later on the reaction product crystallizes out. On thefollowing day the reaction product is separated off at 0 C. and leftdrying. 56.8 g. of the compound of the formula of melting point209.5210.5 C. are obtained. After rccrystallizing from ethanol theproduct melts at 21021 l.5

C H N O (molecular weight 301.30) Calculated: C 55.80% H 5.02% N 23.25%0 15.93%

Found: C 56.1% H 5.1% N 22.7% 016.2%

The 2-[4-methoxy-pyrazolyl-( l )]--amino-benzimidazole used as startingmaterial was prepared as follows: a. 2-[4-methoxy-pyrazol( 1)]-5-nitro-benzimidazole 386 g. (2 moles) of2-hydrazino-5-nitro-benzimidazole, 1588 ml. of water, 412.5 ml. (5moles) of concentrated hydrochloric acid and 300 ml. of methanol arecombined while stirring. 387 g. (3 moles) of 2-methoxy-3-dimethylamino-acrolein are added at 40 C. The temperature rises to 485C. 45 minutes after the beginning of the experiment the mixture isheated up and kept at 80 C. for 2 hours. The precipitated reactionproduct is filtered off with suction at room temperature, washed firstwith water until chlorine-free and then with methanol, dried at first inthe atmosphere and then at 1 C. 306 g. of the compound of melting point229.523 1 C. are obtained. b. 2-[4-methoxy-pyrazolyl-( l)]-5-amino-benzimidazole 259 g. (1 mole) of the nitro compound obtainedaccording to (a) are hydrogenated in 1.8 l. of ethanol in the presenceof 50 g. of Raney nickel with hydrogen gas at 50 C. and a pressure of 60atmospheres. The precipitated reduction product is dissolved by heatingand adding a little dimethylformamide, is separated by suctionfiltration and the product concentrated by evaporation in a water-jetvacuum up to a bath temperature of 90 C. The residue is recrystallizedfrom anisol; the product melts at 21 l212 C.

EXAMPLE 9 The compound of the formula N CH;OCNH

ll CNN U N H l O CH;

of melting point 235235.5 C. is obtained analogously to example 8 from2-[4-methoxypyrazo1yl-(1)]-5-aminobenzimidazole and pyrocarbonic aciddimethyl ester in methanol as solvent.

c u N o (molecular weight 287.27) Calculated: C 54.35% H 4.56% N 24.38%0 16.71% Found: C 54.1% H 4.7% N 24.4% 0 16.8%

EXAMPLE 10 is precipitated from the solution. The product is filteredoff with suction at 0 C washed with petroleum ether and dried. 27.1 g.of melting point 185186.5 C. are obtained. Upon recrystallization fromtoluene the product is obtained with toluene of crystallization which isremoved by dissolving the same in six times the quantity of hotacetonitrile and briefly heated to boil. The solvent-free substanceprecipitates. The substance is filtered off with suction in the cold,washed with ether and dried at 110 C. 17.6 g. of compound of meltingpoint l86l 865 C. are obtained.

C l-l N O (molecular weight 285.30)

Calculated: C 58.93% H 5.30% N 24.55% 0 11.22% Found: C 58.9% H 5.3% N24.4% 011.3%

The amino compound used as starting material was prepared bycondensation of 2-hydrazino-5-nitrobenzimidazole with acetylacetone toyield 2[3,5-dimethylpyrazolyl-(l)]-5-nitro-benzimidazole and subsequentreduction of the nitro group to the amino group; melting point 22l.5-222C.

EXAMPLE 1 l are obtained with ethanol of crystallization which isremoved by gradually raising the drying temperature to 1 10 C. toconstant weight. The preparation melts then at l75-l 75.5 C. C, H,-,N=,O (molecular weight 299.33)

Calculated: C 60.19% H 5.72% N 23.40% 0 10.69%

Found: C 60.0% H 5.7% N 23.3% 0 10.9%

EXAMPLE 12 20.9 g. (0.1 1 mole) of pyrocarbonic acid diisopropyl esterare added dropwise to 22.7 g. (0.1 mole) of 2-[3,5-dimethylpyrazolyl-( l)]-5-amino-benzimidazole in ml. of isopropanol. A solution graduallyforms from which the desired compounds of the formula CH -CH;

is later precipitated with isopropanol of crystallization. The compoundis filtered off by suction at 20 C., washed with petroleum ether andleft drying (29.5 g.). The crystal solvent is removed by dissolving themixture in the smallest possible quantity of boiling acetonitrile,boiling for a short period of time whereupon the solvent-free compoundprecipitates, cooling, isolating at 20 C. and drying at C. The meltingpoint is then at l78.5170 C.

C, H, N O (molecular weight 313.35)

Calculated: C 61.32% H 6.11% N 22.35% 010.21%

Found: C 61.4% H 6.2% N 22.4% 0 10.5%

EXAMPLE [3 47.8 ml. (0.5 mole) of chloroformic acid ethylester are addeddropwise at 05 C within 2.5 hours to a thoroughly stirred mixture of99.5 g. (0.5 mole) of 2-[pyrazolyl-(l)]-5- amino-benzimidazole and 250ml. of pyridine. On the following day ml. of pyridine are distilled offin a vacuum. The paste obtained as residue is stirred with 3 l. of waterwhereupon the reaction product completely precipitates. The product isfiltered off with suction, washed with water and dried at first in theatmosphere and then at 1 10 C. 123 g. of melting point 177.5179 C. areobtained. After recrystallizing from eight times the quantity ofpropionitrile there are obtained l 15 g. of a pure compound of meltingpoint l80.5 C. This compound is identical to the product according toexampie 1 in respect of all properties.

is stirred with 3 l. of water. After some time the desired compound ofthe formula precipitates in solid form. The compound is filtered offwith suction, washed with water and left drying: Yield 57.8 g. The crudeproduct is stirred with 120 ml. of acetonitrile at 70 C. for 1 hour, afurther 50 ml. of acetonitrile are added, the product is filtered off atC., washed with ice cold acetonitrile and left drying. The product (49.0g. of melting point 156158.5 C.) can be recrystallized fromacetonitrile, I

if desired. By recrystallizing the melting point is not raised. C,,,H, NO (301.30)

Calculated: C 55.80% H 5.02% N 23.25% 015.93% Found: C 55.9% H 5.2% N23.2% 0 16.3% 6.3

EXAMPLE 15 30.6 g. (0.25 mole) of chloroformic acid isopropyl ester areadded dropwise while cooling with ice and stirring within 2 hours to amixture of 49.75 g. (0.25 mole) of 2-[pyrazolyl-(l)l-S-amino-benzimidazole and 125 ml. of pyridine. 0n the following day80 ml. of pyridine are distilled off in a vacuum at a bath temperatureof 40C. By stirring the remaining mass with 3 l. of water solidificationoccurs. The mass is filtered off with suction, washed with water anddried. The crude product (67.9 g.) is recrystallized from propionitrile;m.p. 205-206 C. The compound is the higher melting modification of theproduct according to example 7.

EXAMPLE 16 35.75 g. (0.25 mol) of chloroformic acid-B-chloroethyl esterare added dropwise while cooling with ice and stirring to 49.75 g. (0.25mol) of benzimidazole in 125 ml. of pyridine. 0n the following day 45ml. of pyridine are distilled ofi from the reaction mixture at a bathtemperature of at most 49 C. The mass obtained as residue is stirredwith 3 1. of water whereupon recrystallization gradually occurs. Themass is then filtered off with suction, washed with water and dried. 77g. of the crude compound are obtained. The compound is purified bydissolution in 150 ml. of warm dimethylformamide and precipitates whilestirring with 1.5 l. of acetonitrile. The product is filtered off withsuction, washed with ether and dried at 110 C; yield 55 g. of m.p.l89-189.5C.

c n cm o (305.5)

Calculated: C 51.10% H 3,93% CL 11.61% N 22.90% 0 Found: C 51.1% H 4.3%CL 11.4% N 22.7% 010.40%

12 EXAMPLE 17 40.6 g. (0.25 mol) of chloroformic acid cyclohexyl esterare added dropwise within 60 minutes to a solution of 49.75 g. (0.25mol) of 2-[pyrazolyl-(1)I-S-amino-benzimidazole in 200 ml. of pyridinewhich is stirred while cooling with ice. On the following day 140 ml. ofpyridine are distilled off in a vacuum. The mass obtained as a residueis vigorously stirred with 3 l. of water, whereupon the desired compoundof the formula 1! II o l precipitates in solid form. The compound isfiltered off with suction, washed with water and dried at C. The crudeproduct is purified by recrystallization from 15 times the quantity ofpropionitrile and dried at C: yield 66 g. of m.p. 205-206 C.

EXAMPLE 18 The procedure as described in example 17 is followed; however41.1 g. (0.25 mol) of chloroformic acid-n-hexylestcr are used instead ofchloroformic acid eyclohexylester. The desired compound of the formulais obtained in a yield of 76.7 g. of m.p. l23-125 C. Afterrecrystallization once from propionitrile the product is completelypure; m.p. l30-131 C.

What is claimed is: 1. A compound ofthe formula in which Y is hydrogenor lower alkyl. 13 is hydrogen, lower alkyl or lower alkoxy, n is theinteger 1 or 2, and R is straight or branched chain alkyl of one to sixcarbon atoms unsubstituted or substituted by halogen or lower alkoxy oris eycloalkyl of five or six carbon atoms.

2. A compound of claim 1 having the formula:

in which R is straight or branched chain alkyl of one to six carbonatoms unsubstituted or substituted by halogen or lower alkoxy.

3. A compound according to claim 1 wherein Y is hydrogen.

4. A compound according to claim 1 wherein Y is lower alkyl.

5. A compound according to claim 1 wherein B is hydrogen.

6. A compound according to claim 1 wherein B is lower a]- kyl.

7. A compound according to claim 1 wherein B is lower alkoxy.

8. A compound according to claim 1 wherein R is straight or branchedchain alkyl of one to six carbon atoms unsubstituted or substituted byhalogen or lower alkoxy.

9. A compound according to claim 1 wherein R is cycloalkyl of five orsix carbon atoms.

10. A compound according to claim 1 wherein R is haloalkyl of one to sixcarbon atoms.

11. A compound according to claim 1 wherein R is lower alkoxy alkyl ofone to four carbon atoms in the alkoxy moiety and of one to six carbonatoms in the alkyl moiety.

12. A compound according to claim 1 wherein R is lower alkyl of one tosix carbon atoms.

13. A compound according to claim 1 wherein Y is hydrogen or methyl, Bis hydrogen, methyl or methoxy, and R *zgggy UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 3,609,166 Dated September 28, 1971Inventor) Walter Gauss, Heinz Herli nger, Herbert Thomas and KanfredPlempel It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

q In the title, change "BEIQIONIDAZOLES" to BENZIMIDAZOLES In theAbstract, line 8, change"T" to Y line 10, change "notro" to nitro line16, change "n" to in line 19, change "notro" to nitro In Column 1, line1, change "BENZIONIDAZOLES" to BENZIHIDAZOLES Signed and sealed this Lth day of April 1 972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR.

ROBERT GOTTSCHALK Atte sting Officer Commissioner of Patents

2. A compound of claim 2 having the formula:
 3. A compound according toclaim 1 wherein Y is hydrogen.
 4. A compound according to claim 1wherein Y is lower alkyl.
 5. A compound according to claim 1 wherein Bis hydrogen.
 6. A compound according to claim 1 wherein B is loweralkyl.
 7. A compound according to claim 1 wherein B is lower alkoxy. 8.A compound according to claim 1 wherein R is straight or branched chainalkyl of one to six carbon atoms unsubstituted or substituted by haLogenor lower alkoxy.
 9. A compound according to claim 1 wherein R iscycloalkyl of five or six carbon atoms.
 10. A compound according toclaim 1 wherein R is haloalkyl of one to six carbon atoms.
 11. Acompound according to claim 1 wherein R is lower alkoxy alkyl of one tofour carbon atoms in the alkoxy moiety and of one to six carbon atoms inthe alkyl moiety.
 12. A compound according to claim 1 wherein R is loweralkyl of one to six carbon atoms.
 13. A compound according to claim 1wherein Y is hydrogen or methyl, B is hydrogen, methyl or methoxy, and Ris straight or branched chain alkyl of one to six carbon atomsunsubstituted or substituted by chlorine or methoxy or is cyclohexyl.14. The compound of claim 1 which is 2-(pyrazolyl-(1)) -5-methoxy-carbonylamino-benzimidazole.
 15. The compound of claim 1 whichis 2-(pyrazolyl-(1))-5-ethoxy-carbonylamino-benzimidazole.
 16. Thecompound of claim 1 which is2-(pyrazolyl-(1))-5-n-propoxy-carbonylamino-benzimidazole.
 17. Thecompound of claim 1 which is2-(pyrazolyl-(1))5-iso-propoxy-carbonylamino-benzimidazole.